Chronic inflammatory diseases, particularly rheumatic diseases, lead to accelerated atherosclerosis. At the same time, atherosclerosis itself is increasingly recognized as a chronic vascular inflammatory condition. These inflammatory processes induce a wide variety of metabolic changes with two of these changes relating specifically to atherogenesis. The first is the cytokine mediated induction of acute phase serum amyloid A protein (SAA) that increases hundreds of fold and can even become the major apolipoprotein on HDL. A second factor is the concomitant induction of an acute phase extracellular enzyme group II-A secretory phospholipase A2 (sPLA2). Like SAA, the concentration of sPLA2 can increase hundreds of fold in inflammatory fluids or the circulation. Circulating levels of both SAA and sPLA2 predict coronary events in patients with coronary artery disease. Using sPLA2 overexpressing transgenic mouse, direct evidence was presented that this enzyme promotes vascular lipid deposition, even in the absence of a high fat diet. In preliminary data, we present evidence that increased SAA is associated with vascular lipid deposition. Considerable effort was spent analyzing the concomitant influence of SAA and sPLA2 on systemic lipoprotein metabolism. Less emphasis was placed on the potentially important role that these molecules can play in the atherosclerotic lesion per se. Both avidly bind to proteoglycan and accumulate in lesions. Proteoglycan bound sPLA2 promote hydrolysis of a spectrum of lipoproteins, particularly LDL, generating bioactive entities that are proinflammatory. SAA can act as a co-factor for sPLA2. In addition amyloidogenic SAAs are the most fibrillogenic proteins known and can entrap lipoprotein in such networks. The major hypothesis of this proposal is that SAA and sPLA2 act interactively, predominantly at the vascular lesional level, to promote atherogenesis. We propose that SAA and sPLA2, respectively produced by macrophages and smooth muscle cells, is important in amplifying and perpetuating lesional inflammation ultimately promoting vascular lipid deposition.